CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 208271Orig1s000 OTHER REVIEW(S) Reference ID: 3963792 Reference ID: 3963792 Reference ID: 3963792 Reference ID: 3963792 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy PATIENT LABELING REVIEW Date: June 22, 2016 To: Donna Griebel, MD Director Division of Gastroenterology and Inborn Errors Products (DGIEP) Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Marcia Williams, PhD Team Leader, Patient Labeling Division of Medical Policy Programs (DMPP) From: Karen Dowdy, RN, BSN Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Meeta Patel, Pharm.D. Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling: Medication Guide (MG) and Instructions for Use (IFU) Drug Name (established RELISTOR (methylnaltrexone bromide) name): Dosage Form and Route: tablets, for oral use injection, for subcutaneous use Application NDA 208271 Type/Number: Applicant: Salix Pharmaceuticals, Inc., a wholly owned subsidiary of Valeant Pharmaceuticals International, Inc., with its affiliate, Valeant Pharmaceutical North America being the communicant Reference ID: 3949385 1 INTRODUCTION On June 19, 2015, Salix Pharmaceuticals, Inc., a wholly owned subsidiary of Valeant Pharmaceuticals International, Inc., with its affiliate, Valeant Pharmaceutical North America being the communicant, submitted for the Agency’s review 505(b)(1) New Drug Application (NDA) 208271 for RELISTOR (methylnaltrexone bromide) tablets. The proposed indication for RELISTOR tablets is for the treatment of opioid- induced constipation (OIC) in adult patients with chronic non-cancer pain. The Applicant cross-references all data contained in RELISTOR Subcutaneous Injection NDA 021964/S-010 approved for the treatment of OIC in adult patients with chronic non-cancer pain on September 29, 2014. RELISTOR (methylnaltrexone bromide) Subcutaneous Injection NDA 021964 was originally approved on April 24, 2008, for the treatment of OIC in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to the requests by the Division of Gastroenterology and Inborn Errors Products (DGIEP) on June 22, 2015, for DMPP and OPDP to review the Applicant’s proposed Medication Guide (MG) and Instructions for Use (IFU) for RELISTOR (methylnaltrexone bromide) tablets and RELISTOR (methylnaltrexone bromide) injection. 2 MATERIAL REVIEWED • Draft RELISTOR (methylnaltrexone bromide) tablets MG and IFU received on June 19, 2015, revised by the Review Division throughout the review cycle, and received by DMPP and OPDP on June 14, 2016. • Draft RELISTOR (methylnaltrexone bromide) tablets Prescribing Information (PI) received on June 19, 2015, revised by the Review Division throughout the review cycle and received by DMPP and OPDP on June 14, 2016. • Approved RELISTOR (methylnaltrexone bromide) Subcutaneous Injection comparator labeling dated September 29,2014. 3 REVIEW METHODS To enhance patient comprehension, materials should be written at a 6th to 8th grade reading level, and have a reading ease score of at least 60%. A reading ease score of 60% corresponds to an 8th grade reading level. Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in collaboration with the American Foundation for the Blind (AFB) published Guidelines for Prescription Labeling and Consumer Medication Information for People with Vision Loss. The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make medical information more accessible for patients with vision loss. We have reformatted the MG document using the Arial font, size 10. Reference ID: 3949385 In our collaborative review of the MG and IFUs we have: • simplified wording and clarified concepts where possible • ensured that the MG and IFUs are consistent with the Prescribing Information (PI) • removed unnecessary or redundant information • ensured that the MG and IFUs are free of promotional language or suggested revisions to ensure that it is free of promotional language • ensured that the MG and IFUs meet the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006) • ensured that the MG and IFUs are consistent with the approved comparator labeling where applicable. 4 CONCLUSIONS The MG and IFUs are acceptable with our recommended changes. 5 RECOMMENDATIONS • Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence. • Our collaborative review of the MG and IFUs are appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the MG or IFUs. Please let us know if you have any questions. 57 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page Reference ID: 3949385 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- KAREN M DOWDY 06/22/2016 MEETA N PATEL 06/22/2016 LASHAWN M GRIFFITHS 06/22/2016 Reference ID: 3949385 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion Memorandum **PRE-DECISIONAL AGENCY MEMO** Date: June 21, 2016 To: Lawrence Allan Regulatory Project Manager Division of Gastroenterology and Inborn Errors Products From: Meeta Patel, PharmD Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: NDA 208271 OPDP Comments for proposed draft PI, MG, and IFU for RELISTOR® (methylnaltrexone bromide) tablets, for oral use and RELISTOR® (methylnaltrexone bromide) injection, for subcutaneous use OPDP has reviewed the proposed draft PI Relistor. We have no additional comments. Comments on the proposed patient labeling will be submitted under a separate cover as a joint review with DMPP. Thank you for the opportunity to comment on the proposed PI. If you have any questions or concerns, please contact Meeta Patel at 301-796-4284 or [email protected]. 57 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page Reference ID: 3949074 --------------------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------- /s/ ---------------------------------------------------- MEETA N PATEL 06/21/2016 Reference ID: 3949074 DATE: June 9, 2016 FROM: Robert Ball, MD, MPH, ScM, Deputy Director, Office of Surveillance and Epidemiology, CDER, FDA SUBJECT: Oral Relistor ARIA Sufficiency Memo I concur with the lack of sufficiency of ARIA for evaluating this oral Relistor safety issue and make the following observations. 1) The standards against which ARIA sufficiency are being compared are those for Safety Outcome Trials and the FDA Best Practice Guidance for Conducting and Reporting Pharmacoepidemiology Safety Studies Using Electronic Healthcare Data. These are very high standards but the decision to use those standards is the key to this determination. 2) The justification for using these standards in this particular situation is well described in the memo, but is relatively unique to this situation’s scientific and regulatory history and may not apply in future situations. 3) In several of the findings of lack of sufficiency (e.g. missing information on out of hospital deaths and behavioral and preventive practices of study patients), the lack of information in itself is considered grounds for lack of sufficiency. A more nuanced approach would involve assessing the quantitative impact of the lack of information, and the potential for biased findings, relative to the effect size of interest and should be considered for future sufficiency determinations. 4) The lack of sophisticated diagnostics for assessing statistical model appropriateness is cited as a reason for lack of sufficiency. This might be the most easily solved of the cited issues and whether it can be remedied in the ARIA tools is worth exploring. Page 1 of 14 Reference ID: 3944153 Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research| Office of Surveillance and Epidemiology (OSE) Epidemiology: ARIA Sufficiency Memo Version: 2016-02-11 Date: June 9, 2016 Reviewer(s): Joel L. Weissfeld, MD MPH, Medical Officer Division of Epidemiology I Team Leader: Sukhminder K. Sandhu, PhD MPH MS Division of Epidemiology I Deputy Division Director: David Shih, MD MS Division of Epidemiology I Subject: ARIA Sufficiency Memo Drug Name(s): methylnaltrexone bromide tablet (Relistor®) Application Type/Number: NDA 208271 (IND 067452) Applicant/sponsor: